Prognostic Factors Of Small Cell Lung Cancer

Objective1.Approximately 30 to 40 percent of small cell lung cancer(SCLC)is imited-stageSCLC(LS-SCLC)at first clinical presentation.The median ranges of survival for LS-SCLC are 15 to 20 months.Approximately 20 to 40 percent of LS-SCLC patients can survive longer than two years,which is considered as"long-term"survival in SCLC.In the last a few decades,a modest yet significant improvement of the survival rate of LS-SCLC has been shown in North America and other countries.Combined modality therapy is the standard care for limited stage-small cell lung cancer(LS-SCLC)and has led to a significant improvement in patients' survival.This study sought to investigate and define the importance of prognostic effects of known and controversial factors especially the impact of smoking status and treatment strategies.2.Small cell lung cancer(SCLC)carries the worst prognosis among various types of lung cancer.Combined radiation and chemotherapy is the standard of care;however, outcomes from the treatment vary.Metabolic rate of chemotherapy agents and DNA repair capability may be partly responsible for this variation in treatment response.This study selected tagSNPs from genes in the glutathione synthesis and DNA repair pathways to test their association with survival in patients with SCLC.Materials and Methods1.A total of 284 patients with LS-SCLC diagnosed and prospectively followed from 1997 to 2008 at Mayo Clinic.Two groups in this cohort,short-term survivors(＜2 years,n=163)and long-term survivors(＞2 years,n=121),we also subcategorized patients according to their duration of smoking abstinence at the time of diagnosis and during follow-up.Five groups were defined as follows:(1)quit greater than or equal to 10 years prior to diagnosis or never smokers,(2)quit for 3-9 years,(3)quit for 1-2 years,4)quit at or after diagnosis,and(5)did not quit.The cigarette"dose"or "intensity"categories were defined as self-reported packs per day(PPDs)as well as the total number of pack-years of smoking history,were assessed on the basis of age, gender,smoking history,performance score(PS),tumor recurrence or progression,and treatment using Cox proportional hazards models.2.Blood DNA from 248 patients with primary SCLC(diagnosed 1997-2006)was genotyped for tagSNPs from 49 genes in glutathione and DNA repair pathways.We included genes in the glutathione pathway as described previously.Twenty nine genes, including isozymes and membrane bound transporter proteins,were selected.An additional twenty genes were selected from the DNA repair pathway following a review of the literature that reported association with treatment response or survival in lung or other cancers.Four hundred nineteen tagSNPs,267 from the glutathione and 152 from DNA repair pathway,were genotyped using a custom-designed Illumina GoldenGate panel.Call rates were obtained for each of the SNPs and Hardy-Weinberg equilibrium was assessed.SNPs with call rate less than 95%or not in Hardy-Weinberg equilibrium or monomorphic in this study population were excluded for further analysis. Clinical characteristics of the 248 patients were first summarized by vital status. Clinical variables were assessed on their association with survival in order to assess the need to be included as adjustment variables in the primary genetic analyses.We obtained Kaplan-Meier curves for each covariate,and performed a stepwise selection process using Cox proportional hazards regression.Association analyses with patient survival were performed at the single SNP,whole gene,and haplotype levels after adjusting for conventional clinical covariates.Results1.Age,sex,smoking cessation,recurrence or progression,chemotherapy started after one month,combined chemoradiotherapy,and PCI varied significantly between the two survival groups(TableⅠ).Younger patients were more likely to live longer than two years.More women survived greater than two years than men did.Smoking status and pack-years smoked were not significantly different between the two groups; however,smoking cessation showed a positive impact on survival.LS-SCLC patients with recurrence or progression during treatment had shorter survival.There was no significant difference for early or late TRT between the two groups,while more patients survived greater than two years when chemotherapy was initiated after one month of diagnosis.Combined chemoradiotherapy and PCI improved prognosis. Different chemotherapy combinations did not show significant impact on survival.(1) Although neither smoking status(former or current smokers) nor intensity (pack-years smoked) at the time of SCLC diagnosis were significant survival predictors, compared to continued smokers(who never quit smoking),patients who quit at or after diagnosis cut the risk of death by 50%(HR=0.50,95%CI 0.36-0.77).(2) Thoracic radiotherapy and platinum-based chemotherapy could significantly improve survival but the timing(within or after 1 month of diagnosis) of starting chemotherapy or radiation therapy did not.(3) After adjusting for other known factors, lower PS did not predict poorer survival.2.Among the 375 SNPs successfully genotyped,21 showed significant association with survival after adjusting for age,gender,tumor stage,treatment modalities,and smoking history.These 21 SNPs are located on 11 genes(7 in glutathione and 4 in DNA repair pathways).Whole-gene analyses confirmed three of the 11 genes:the GSS,ABCC2 and XRCC1 and haplotype analyses of these three genes identified haplotype combinations and genomic locations underlying the observed SNP associations.Further analyses identified several haplotypes within GSS and ABCC2 were significantly positive associated with overall survival of SCLC.And within XRCC1,among the 5 SNPs in our data,one is(rs100158) correlated with increased and another(rs2854510) is associated with decreased survival in SCLC.Conclusion1.This study demonstrated the negative impact of continued cigarette smoking on survival;therefore,clinicians and all care providers should strongly encourage smoking cessation at diagnosis of LS-SCLC.2.Genetic variation in genes involved in the glutathione pathway and DNA repair is associated with outcomes of SCLC after treatment.